The Alzheimer's Disease Research Center (ADRC) at The Johns Hopkins Medical Institutions (JHMI) is committed to investigations of aging and Alzheimer's disease (AD). Age and genes are important risk factors for AD, and our principal goal is to examine the impact of age and mutations in the amyloid precursor protein (APP) in the cognition/memory abnormalities occurring in elderly humans and in our mouse/human-APPswe (Mo/Hu- APP) transgenic (Tg) mice. Thus, with the support of Cores A and D, Cores B and C focus on behavior-brain correlations in intact, mildly impaired, and demented aged individuals, particularly by those in the cohorts of the Baltimore Longitudinal Study of Aging (BLSA). This extraordinarily well characterized with serial imaging studies; many of these individuals have entered our prospective autopsy program. Supported by Cores B and C, Project 4 takes advantage of this material to examine early brain lesions focusing on: glial cell responses and the production of inflammatory mediators. complement factors, cytokines, etc.) capable of influencing neurons and synapses. These findings will be correlated with detailed assessments of the neuropathology, quantitative estates of synaptic markers, and evidence of cell death and neuronal loss. In parallel to the studies of aging and AD in humans, Projects 1-3 take advantage of our lines of Mo/Hu-APPswe Tg mice that express mutant APP at levels approximately threefold greater than endogenous MoAPP; these animals develop Abeta deposits, we hypothesize that elevated levels of Abeta42 damage synapses before over deposits of Abeta species. In project 1, we will examine the performances of these Tg mice on tasks designed to assess cognition/memory. In Project 2, we will correlate these findings with studies of biochemical marker (e.g. levels of Abeta peptide species, synaptic proteins, neurotransmitters and their enzymes) and the character/severity of the cellular pathology (e.g., abnormalities in synapses, Abeta deposition, loss of synapses, activation of glial cells, subsets of neurons, evidence of cell death, etc.) in specific regions of brain. In Project 3, we believe that these parallel clinical-neurochemical-pathological correlative studies of humans and Tg mice will help to define the biological substrates of impairments. In the intervention studies of our Tg mice, we will assess the responsivity (to age, genotype, and toxins) to the basal forebrain cholinergic and monoaminergic systems that are vulnerable in cases of AD; attempt to provoke glial cells to enhance amyloid; and to test the effects of estrogen on Abeta deposits. Finally, Core D will serve to disseminate information concerning age-associated diseases to families, caregivers, and other health professionals.